Modeling the Prognostic Impact of Circulating Tumor Cells Enumeration in Metastatic Breast Cancer for Clinical Trial Design Simulation.

Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 individual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and its prognostic impact resulted in a hazard ratio (HR) of 1.89 (Simulatedaggressive vs SimulatedindolentP < .001), similar to patients with actual CTCs enumeration (HR 2.76; P < .001). The classifier's performance was then tested on an independent retrospective database comprising 446 consecutive hormone receptor (HR)-positive HER2-negative MBC patients. The model further stratified clinical subgroups usually considered prognostically homogeneous such as patients with bone-only or liver metastases. Bone-only disease classified as Simulatedaggressive had a significantly worse overall survival (OS; P < .0001), while patients with liver metastases classified as Simulatedindolent had a significantly better prognosis (P < .0001). Consistent results were observed for patients who had undergone CTCs enumeration in the pooled population. The differential prognostic impact of endocrine- (ET) and chemotherapy (CT) was explored across the simulated subgroups. No significant differences were observed between ET and CT in the overall population, both in terms of progression-free survival (PFS) and OS. In contrast, a statistically significant difference, favoring CT over ET was observed among Simulatedaggressive patients (HR: 0.62; P = .030 and HR: 0.60; P = .037, respectively, for PFS and OS).

Anamorelin combined with physical activity, and nutritional counseling for cancer-related fatigue: a preliminary study.

PURPOSE: Cancer-related fatigue (CRF) is the most frequent and debilitating symptom in patients with advanced cancer. There are limited effective treatments for CRF. The objective of this prospective longitudinal study was to evaluate the change in CRF at Day 43 after treatment with combination therapy of oral Anamorelin 100 mg daily with physical activity and nutrition counseling. METHODS: In this study, patients with CRF [≤ 34 Functional Assessment of Chronic Illness Therapy-Fatigue subscales(FACIT-F)] received Anamorelin 100 mg orally daily with standardized physical activity and nutrition counseling for 43 days. Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Anorexia Cachexia(FAACT-ACS), Multidimensional Fatigue Symptom Inventory-Short Form(MFSI-SF), Patient-Reported Outcomes Measurement Information System(PROMIS-Fatigue), body composition, and physical performance tests were assessed at baseline, Day 15, 29, and 43. Frequency and type of side effects were determined by NCI CTAE 4.0.(NCT03035409). RESULTS: 28/45 (62%) of patients dosed were evaluable at Day 43. The mean, SD for FACIT-F subscale improvement from baseline was 4.89 (± 13.07), P = .058, MFSI-SF (G) - 3.46 (± 6.86), P = 0.013, PROMIS-fatigue - 4.14 (± 7.88), P = 0.010, FAACT ACS 3.48 (± 8.13), P = 0.035. Godin Liesure-Time physical activity questionnaire 7.41 (± 16.50), P = 0.038. Weight (kg) 1.81 (± 2.63), P = 0.005, and Lean Body Mass 1.54 (± 1.85), P = 0.001, IGF-1 36.50 (± 48.76), P = 0.015. There was no significant improvement in physical performance outcomes. No adverse events > grade 3 related to the study drug were reported. CONCLUSION: The use of the combination therapy was associated with improvement of CRF (FACIT-F fatigue, PROMIS-fatigue, MFSI-SF-general), activity (Godin-leisure time), anorexia (FAACT), body composition, and IGF-1 levels. Further studies using combination therapy for CRF are justified.

Prostate cancer cells survive anti-androgen and mitochondrial metabolic inhibitors by modulating glycolysis and mitochondrial metabolic activities.

BACKGROUND: Most cancer cells are more glycolytic even under aerobic conditions compared with their normal counterparts. Recent evidence of tumor cell metabolism, however, shows that some tumors also increase mitochondrial oxidative phosphorylation (ox-phos) at some disease states during progression and/or development of drug resistance. Our data show that anti-androgen enzalutamide (ENZA) resistant prostate cancer (PCa) cells use more mitochondrial metabolism leading to higher ox-phos as compared to the ENZA-sensitive cells and can become vulnerable to mitochondrial metabolism targeted therapies. METHODS: Seahorse assay, mass spectrometry and high resolution fluorescence confocal microscopy coupled with image analysis has been used to compare mitochondrial metabolism in ENZA-treated and -untreated anti-androgen-sensitive LNCaP and -resistant C4-2, CWR22ν1, and PCa2b cells. Ex vivo fluorescence microscopy and image analysis has been standardized to monitor mitochondrial electron transport (ETS) activity that likely increases ox-phos in circulating tumor cells (CTCs) isolated fom patients undergoing AR-targeted therapies. RESULTS: Our data show that PCa cells that are resistant to anti-androgen ENZA switch from glycolysis to ox-phos leading to an increased ETS activity. ENZA pretreated cells are more vulnerable to ETS component complex I inhibitor IACS-010759 (IACS) and mitochondrial glutaminase inhibitor CB-839 that reduces glutamate supply to tricarboxylic acid cycle. CTCs isolated from 6 of 20 patient blood samples showed relatively higher ETS activity than the rest of the patients. All six patients have developed ENZA resistance within less than 6 months of the sample collection. CONCLUSION: The enhanced growth inhibitory effects of mitochondrial metabolic inhibitors IACS and CB-839 in ENZA pretreated PCa cells provides a rationale for designing a drug combination trial. Patients can be selected for such trials by monitoring the mitochondrial ETS activities in their CTCs to maximize success.

Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. METHODS: We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. RESULTS: We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. CONCLUSIONS: Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15's dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC.

Combination Therapy of Physical Activity and Dexamethasone for Cancer-Related Fatigue: A Phase II Randomized Double-Blind Controlled Trial.

BACKGROUND: Despite the high frequency of cancer-related fatigue (CRF) and its debilitating effects on the quality of life of patients with advanced cancer, there are limited treatment options available. Treatments including physical activity (PA) or dexamethasone (Dex) improve CRF; however, they have lower adherence rates (PA) or long-term adverse effects (Dex). The aim of this study was to determine the feasibility of and preliminary results for the combination of PA and Dex in improving CRF. METHODS: In this phase II randomized controlled trial, patients with advanced cancer and CRF scores of ≥4/10 on the Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks with either 4 mg of Dex (LoDex arm) or 8 mg of Dex (HiDex arm) twice a day for 7 days. Feasibility and change in the Functional Assessment of Cancer Illness Therapy-Fatigue subscale (FACIT-F) from baseline to day 8 and day 29 (primary outcome) were assessed. Secondary outcomes included changes in fatigue dimensions (FACIT-General, Patient-Reported Outcomes Measurement Information System [PROMIS]-Fatigue). RESULTS: A total of 60 of 67 (90%) patients were evaluable. All patients were adherent to study medication. We found that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The FACIT-F effect size in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and the effect size in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. We found significant improvements in the Functional Assessment of Cancer Therapy-Physical (P≤.013) and the PROMIS-Fatigue (P≤.003) at days 8 and 29 in both arms. Mixed-model analysis showed a significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F scores were not significantly different between patients in the 2 arms (P=.86). CONCLUSIONS: Our study found that the combination therapy of PA with Dex was feasible and resulted in the improvement of CRF. The improvement was seen for up to 3 weeks after the discontinuation of Dex. Further larger studies are justified. CLINICALTRIALS: gov identifier: NCT02491632.

Correction to: A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer.

An amendment to this paper has been published and can be accessed via the original article.

A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer.

BACKGROUND: Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. METHODS: In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24-/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry. RESULTS: Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24-/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. CONCLUSIONS: Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

Cancer associated macrophage-like cells and prognosis of esophageal cancer after chemoradiation therapy.

BACKGROUND: Cancer Associated Macrophage-Like cells (CAMLs) are polynucleated circulating stromal cells found in the bloodstream of numerous solid-tumor malignancies. Variations within CAML size have been associated with poorer progression free survival (PFS) and overall survival (OS) in a variety of cancers; however, no study has evaluated their clinical significance in esophageal cancer (EC). METHODS: To examine this significance, we ran a 2 year prospective pilot study consisting of newly diagnosed stage I-III EC patients (n = 32) receiving chemoradiotherapy (CRT). CAML sizes were sequentially monitored prior to CRT (BL), ~ 2 weeks into treatment (T1), and at the first available sample after the completion of CRT (T2). RESULTS: We found CAMLs in 88% (n = 28/32) of all patient samples throughout the trial, with a sensitivity of 76% (n = 22/29) in pre-treatment screening samples. Improved 2 year PFS and OS was found in patients with CAMLs < 50 µm by the completion of CRT over patients with CAMLs ≥ 50 µm; PFS (HR = 12.0, 95% CI = 2.7-54.1, p = 0.004) and OS (HR = 9.0, 95%CI = 1.9-43.5, p = 0.019). CONCLUSIONS: Tracking CAML sizes throughout CRT as a minimally invasive biomarker may serve as a prognostic tool in mapping EC progression, and further studies are warranted to determine if presence of these cells prior to treatment suggest diagnostic value for at-risk populations.

Elevated serum levels of sialyl Lewis X (sLeX) and inflammatory mediators in patients with breast cancer.

PURPOSE: The carbohydrate sialyl LewisX (sLeX) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLeX and inflammatory cytokines/chemokines in breast cancer sera. METHODS: We retrospectively measured sLeX and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLeX and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLeX using a cut-off of 8 U/mL as previously defined. RESULTS: Median serum sLeX was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLeX > 8 U/mL have a significantly shorter progression-free survival (PFS) (P = 0.0074) and overall survival (OS (P = 0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P = 0.001 and P < 0.001, respectively) and PFS (P = 0.010 and P < 0.001, respectively). sLeX, MCP-1 and IP-10 remained significant in multivariate survival analysis. CONCLUSION: Elevated serum sLeX was associated with invasive cancer but not DCIS. High serum sLeX levels were associated with inflammatory mediators and may play a role in facilitating local invasion of breast tumor. Furthermore, serum MCP-1, IP-10 and sLeX may have prognostic value in breast cancer.

Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer.

Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy. IMPLICATIONS FOR PRACTICE: This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

INTRODUCTION: We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. MATERIALS AND METHODS: Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. RESULTS: 8 of 8 IBC samples expressed isolated CD44+CD49f+CD133/2+ stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). CONCLUSIONS: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

Inflammatory breast cancer: a proposed conceptual shift in the UICC-AJCC TNM staging system.

In the absence of histological criteria that distinguish between inflammatory and non-inflammatory breast cancer, diagnosis of inflammatory breast cancer relies entirely on the existence of clinical criteria as outlined by the TNM classification. This classification restricts patients presenting with clinical criteria characteristic of inflammatory breast cancer to subcategory T4d, which immediately relegates all patients with non-metastatic inflammatory breast cancer to stage 3, regardless of tumour size or nodal spread. Patients who present with metastatic disease are consigned to stage 4, and the TNM classification does not distinguish patients on the basis of the presence of inflammatory criteria. Evidence by our group and others suggests that patients with inflammatory breast cancer have significantly reduced overall survival among those who present with distant metastasis at diagnosis (stage 4). In light of these results, this Personal View addresses whether the current TNM staging classification accurately represents a distinction between patients with inflammatory and those with non-inflammatory breast cancer.

Thrombocytosis as a prognostic factor in inflammatory breast cancer.

PURPOSE: Platelets are essential components of hemostasis and also play an important role in the tumor microenvironment. The purposes of our research were to examine the role of thrombocytosis in inflammatory breast cancer (IBC) and to know which cytokine drives thrombocytosis. METHODS: We reviewed the medical records of 3654 patients with stage I-III breast cancer treated between 1998 and 2013, including 230 patients (6%) with IBC. We used Chi-squared test or Fisher's exact test to compare the variables between patients with and without thrombocytosis. Multivariate Cox regression models were used to determine the association of thrombocytosis with overall survival. We also examined baseline serum cytokine levels in 81 patients with primary IBC to determine the association of inflammatory cytokines with thrombocytosis. RESULTS: We found that thrombocytosis was the only variable that predicted prognosis. Fifty-five patients (1.5%) had thrombocytosis. Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC (3.4% vs. 1.4%, p = 0.015). In patients with IBC, thrombocytosis was associated with worse overall survival [hazard ratio 2.38, 95% confidence interval (CI) 1.05-5.4, p = 0.0378]. Circulating levels of growth-regulated oncogene (GRO) (odds ratio 1.003, 95% CI 1.001-1.005, p = 0.0019) and transforming growth factor ß (TGF-ß) (odds ratio 1.3, 95% CI 1.128-1.499, p = 0.0003) were associated with thrombocytosis. CONCLUSIONS: Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC and it was associated with poor prognosis. GRO and TGF-ß were associated with thrombocytosis in IBC.

Identification of frequent somatic mutations in inflammatory breast cancer.

PURPOSE: Inflammatory breast cancer is an aggressive form of breast cancer that shows distinct clinical features from non-inflammatory breast cancer. Genomic understanding of inflammatory breast cancer will shed light on biological targets for this disease. Our objective was to identify targeted hotspot mutations using multiplex genome sequencing in inflammatory breast cancer and compare the findings with those for patients with non-inflammatory breast cancer to further recognize novel targets. METHODS: We studied 400 patients with metastatic breast cancer who had somatic hotspot mutation testing using a 46- or 50-gene multiplex platform from March 2012 to December 2014. Among this population, 24 patients had inflammatory breast cancer and 376 patients had non-inflammatory breast cancer. We tested a total of 26 samples from 24 patients with inflammatory breast cancer. RESULTS: The average number of mutations per patient was higher in inflammatory breast cancer than in non-inflammatory breast cancer (1.23 vs. 0.65, respectively). Identified somatic mutations in inflammatory breast cancer were TP53 (n = 18, 75%), PIK3CA (n = 10, 41.7%), and ERBB2 (n = 4, 16.7%). TP53 and ERBB2 mutations were significantly more prevalent in inflammatory breast cancer than in non-inflammatory breast cancer (P < 0.01). All patients with ERBB2 mutations had hormone receptor (HR)+ primary tumors. CONCLUSIONS: TP53, PIK3CA, and ERBB2 were detected as three major somatic mutations in metastatic inflammatory breast cancer patients. While the inflammatory breast cancer TP53 and PIK3CA mutations mirrored previously reported data for metastatic non-inflammatory breast cancer, this is the first report of higher frequency of ERBB2 mutation in inflammatory breast cancer, especially in the HR+ subtype. Once validated in a larger cohort of inflammatory breast cancer patients, this novel finding could lead to development of treatments for HR+ inflammatory breast cancer.

Poor prognosis of patients with triple-negative breast cancer can be stratified by RANK and RANKL dual expression.

PURPOSE: As clinical studies have correlated RANK expression levels with survival in breast cancer, and that RANK signaling is dependent on its cognate ligand RANKL, we hypothesized that dual protein expression further stratifies the poor outcome in TNBC. METHODS: RANK mRNA and protein expression was evaluated in TNBC using genomic databases, cell lines and in a tissue microarray of curated primary tumor samples derived from 87 patients with TNBC. RANK expression was evaluated either by Mann-Whitney U test on log-normalized gene expression data or by Student's t test on FACS data. Analysis of RANK and RANKL immunostaining was calculated by H-score, and correlations to clinical factors performed using χ 2 or Fisher's exact test. Associations with RFS and OS were assessed using univariate and multivariate Cox proportional hazard models. Survival estimates were generated using the Kaplan-Meier method. RESULTS: In three distinct datasets spanning 684 samples, RANK mRNA expression was higher in primary tumors derived from TNBC patients than from those with other molecular subtypes (P < 0.01). Cell surface-localized RANK protein was consistently higher in TNBC cell lines (P = 0.037). In clinical samples, TNBC patients that expressed both RANK and RANKL proteins had significantly worse RFS (P = 0.0032) and OS (P = 0.004) than patients with RANK-positive, RANKL-negative tumors. RANKL was an independent, poor prognostic factor for RFS (P = 0.04) and OS (P = 0.01) in multivariate analysis in samples that expressed both RANK and RANKL. CONCLUSIONS: RANK and RANKL co-expression is associated with poor RFS and OS in patients with TNBC.

Higher Stem Cell Dose Infusion after Intensive Chemotherapy Does Not Improve Symptom Burden in Older Patients with Multiple Myeloma and Amyloidosis.

Autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM) is associated with high symptom burden, particularly for older patients and those with amyloid light-chain (AL) amyloidosis. Symptom burden peaks during leukopenia. We hypothesized that higher doses of CD34(+) stem cells would be associated with an improved symptom outcome. Patients undergoing ASCT for MM who were ≥60 years old or had AL amyloidosis were randomized to receive either a standard (4 to 6 × 10(6) cells/kg) or high dose (10 to 15 × 10(6) cells/kg) of CD34(+) cells after melphalan 200 mg/m(2). Symptom burden was assessed via the MD Anderson Symptom Inventory MM module. Eighty patients were enrolled. Median CD34(+) cell doses were 5.1 × 10(6) cells/kg (standard dose) and 10.5 × 10(6) cells/kg (high dose). The most severe symptoms during the first week were fatigue, lack of appetite, drowsiness, disturbed sleep, and pain. The area under the curve for the mean composite severity score of these symptoms was similar between treatment arms (P = .819). Median times to neutrophil, lymphocyte, and platelet engraftment were also similar between groups. IL-6 increased similarly for both groups throughout the ASCT course. Infusion of higher autologous stem cell dose after high-dose chemotherapy does not yield a difference in symptom burden or engraftment time in the first few weeks after ASCT.

Circulating tumor cells in newly diagnosed inflammatory breast cancer.

INTRODUCTION: Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC. METHODS: This retrospective study included 147 patients with newly diagnosed IBC (77 with locally advanced and 70 with metastatic IBC) treated with neoadjuvant therapy or first-line chemotherapy during the period from January 2004 through December 2012 at The University of Texas MD Anderson Cancer Center. CTCs were detected and enumerated by using the CellSearch system before patients were started with chemotherapy. RESULTS: The proportion of patients with ≥1 CTC was lower among patients with stage III than among patients with metastatic IBC (54.5% versus 84.3%; P=0.0002); the proportion of patients with ≥5 CTCs was also lower for stage III than for metastatic IBC (19.5% versus 47.1%; P=0.0004). Patients with fewer than five CTCs had significantly better progression-free survival (PFS) (hazard ratio (HR)=0.60; P=0.02) and overall survival (HR=0.59; P=0.03) than patients with five or more CTCs. Among patients with stage III IBC, there was a nonsignificant difference in PFS (HR=0.66; 95% confidence interval (CI), 0.31 to 1.39; P=0.29) and OS (HR=0.54; 95% CI, 0.24 to 1.26; P=0.48) in patients with no CTCs compared with patients with one or more CTCs. In multivariate analysis, CTC was prognostic for PFS and OS independent of clinical stage. CONCLUSIONS: CTCs can be detected in a large proportion of patients with newly diagnosed IBC and are a strong predictor of worse prognosis in patients with newly diagnosed IBC.

Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia.

We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71% and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of ß-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p.

Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia.

Noncoding RNAs play a pivotal role in the pathogenesis of chronic lymphocytic leukemia (CLL). We hypothesized that microRNAs (miRs) are involved in the transition from monoclonal B-cell lymphocytosis (MBL) to CLL and tested miR-15a/16-1 cluster, miR-21, and miR-155 expression in purified B cells of normal individuals, individuals with MBL, and patients with CLL. When we analyzed 224 samples from 2 independent training and validation cohorts, we found that miR-155 was overexpressed in B cells from individuals with MBL, and even more so in B cells from patients with CLL, when compared with B cells from normal individuals. Furthermore, we were able to identify miR-155 in circulating microvesicles from both individuals with MBL and patients with CLL. Next, to examine the prognostic role of miR-155, we measured its expression level in plasma samples collected before treatment initiation in 228 patients with CLL. We found significantly higher miR-155 expression levels in patients who failed to achieve a complete response compared with those who experienced complete response. Our findings support the use of cellular and plasma levels of miR-155 as biomarkers for the risk of progression in individuals with MBL, as well as to identify patients with CLL who may not respond well to therapy.

Breast cancer circulating biomarkers: advantages, drawbacks, and new insights.

As of today, the level of individualization of cancer therapies has reached a level that 20 years ago would be considered visionary. However, most of the diagnostic, prognostic, and therapy-predictive procedures which aim to improve the overall level of personalization are based on the evaluation of tumor tissue samples, therefore requiring surgical operations with consequent low compliance for patients and high costs for the hospital. Hence, the research of a panel of circulating indicators which may serve as source of information about tumor characteristics and which may be obtainable by a simple withdrawal of peripheral blood today represents a growing field of interest. This review aims to objectively summarize the characteristics of the currently available breast cancer circulating biomarkers, also providing an overview about the multitude of novel potential soluble predictors which are still under evaluation. Specifically, the usefulness of a so-called "liquid biopsy" will be discussed in terms of improvements of diagnosis, prognosis, and therapy-prediction, but an overview will be given also on the potentiality of the molecular characterization arising from the isolation of circulating biomarkers and cells. Although this review will focus on the specific case of the breast, in the future liquid biopsies will hopefully be available for virtually any type of neoplasms.